Synthesis of compounds having vitamin a activity



Patented Apr. 6, 1954 c UNITED STATES T OFFICE SYNTHESIS OF COMPOUNDSHAVING VITAMIN A ACTIVITY William Oroshnik, 'Plainfield, Nr iLy-assignor=to Ortho Pharmaceutical Corporation a corporation of New Jersey NoDrawing. Application October 3, 1947, SerialJNo. 777;862

15 Claims. (01. 2604488) 1 '2 This invention relates to compositions ofmatan etheror a 154 chlorohydrin o1 isoprene acter and to methods'forpreparing the same. This cording to the followin equation: inventionparticularly relates to compounds which are derivatives ofa-ethynyl-fi-ionol and to methods of preparing the said derivatives. 5

It is an object of this invention to prepare compounds to be used asintermediates in the preparation of compounds having vitamin A activity.

It is another object-of this invention to pre- CH3 Cm CH3 pare compoundshaving the same number of car- 1 l bon atoms and the same configurationwith re- CH=CH C=C""CHC=CH OHWOCH spect to carbon atoms as vitamin Aethers or O esters.

It is another obj ect'of this invention to prepare H1 hydroxy compoundshaving the same number of The acetylenic compound could not be distilledcarbon atoms and the same configuration with ith t dehydration becauseof impurities which respect to carbon atoms as vitamin A ethers-or werent, Th reduction product of the CH: C

esters. acetylenic compound could be converted to a It is still anotherobject of this invention to compound having vitamin A activity by asimulp pare a yd xy p u d having t some tane'ous rearrangement'anddehydration. number of carbon atoms and the same config- As" shown inthe publication cited above, the uration with respect to carbon atoms asvitainventor has discoveredcertain new derivatives min A or a vitamin Aether'which has vitamin A of e-ethynyl-p-ionol and a method 'for theiractivity and rk d Stability to oxidation. preparation. It has now beenfurther discovered It is another and further object of this inventhatthe said derivatives of u-ethynyl-fl-ionol tion to prepare compoundshaving the same maybe prepared in excellent yields and that they numberof carbon atoms and the same conmay be prepared free from impurities andstable figuration withirespeot o C r atoms as Vitato distillation.It-has also been discovered that min A esters or ethers and the samenumber of 3 esters of -a'1,4 ha'lohy'drin of isoprene, as-well as y ogenatoms as vitamin A esters or ethers. the correspondingethers, may beused in the re- It is another object of this inventionto prepare actionwith a-ethynyl-fl-ionol and that thereby compounds having v tam A ctynew and analogous derivatives having a termi- Other objects of thisinvention will be apparnal st group may be obtained. entfrom th d s p flowin and from the It has been *further discovered that the saidappended claims. derivatives of a-ethynyl-fi-ionol may be isomer- In theJournal of the American Chemical ized and dehydrated or dehydrated andisomer- Society, vol me 67, page 1627 (1945), the inized to formadditionalderivatives which have ventor disclosed that certainderivatives of vitaminAactivity.

or-ethynyl-p-ionol have value as intermediates in 40 In the practice ofthis invention. an sacetylenic the preparation of synthetic compoundshaving carbinol,

vitamin A activity. This publication disclosed that a compound havingthe following formula: ('33! H1 o11:011-c-'oo o'Ho=oHoHi-X CHa CH2 6HCH3 I (EH3 1H: OH: 2 cH=oH-c-on=cH-oH, o=oH oHi-ocH, q, I

OH in whichXis OR or H2 -CH:

0 Hg P:

could be prepared by catalytic reduction of and Bus a" hydrocarbonradical, may be prepared an acetylenic compound prepared by reactingbyeitlierof'two routes. wethynyI-p-ionoI with aGrignara reagent andIntheflrst andpreferred'rout'e u-ethynyl-pionol is reacted with areagent such as a metal alkyl in which the metal is a member of thefirst group, preferred reagents being CHsLi and C4H9Li; or a metal alkylin which the metal is a member of the second group such as zinc ormagnesium. When zinc is the metal, the reagent may be a zinc dialkylsuch as (CH3)2Z1'1 or an alkyl zinc iodide such as CI'hZnI; and whenmagnesium is the metal, the reagent may be dialkyl magnesium such as(C2H5)2Mg or a Grignard reagent such as CzHsMgBr. The Grignard reagentis preferred.

The reagent may be considered as having the following general formula:(R').1:MY, in which R is a hydrocarbon radical, such as methyl, ethyl,benzyl, and the like; a: is an integer not greater than two; M is ametal having a valence not greater than two, and Y is a halogen if a: isone and the valence of the metal is two; but Y is nonexistent if M is ametal having a valence of one or if M is a metal having a valence of twoand a: is two.

a-Ethynyl-B-ionol may be prepared in a number of difierent ways and inparticular by reacting B-ionone with calcium or lithium acetylide in aninert solvent as set forth in my U. S. Patent No. 2,425,201, filedSeptember 11, 1945, and issued August 5, 1947; and in my copendingapplication Serial No. 655,607, filed March 19, 1946, now U. S. PatentNo. 2,472,310.

The product of this first reaction is represented by the formula:

CH; CH

a H2 CH=CHCCEC-MYR' OMYR' Ha -CHI Compound II H2 in which M, Y, and Bhave the same significance as above; but in which Y and R. arenonexistent if M is a metal having a valence of one, R is nonexistent ifM is a metal having a valence of two and Y is a halogen, and Y isnonexistent if M is a metal having a valence of two and R is ahydrocarbon radical. In the preferred embodiment MY is MgBr and R isnonexistent or M is a metal having a valence of one and Y and R, arenonexistent. In the single preferred practice or embodiment MY is MgBrand R is nonexistent. The preparation of this compound is described inmy copending U. S. application Serial No. 657,912, filed March 28, 1946,now abandoned. Compound II is reacted with an ether or ester of a 1,4halohydrin of isoprene represented by the formula in which Z is ahalogen, X is OR or ets and R is a hydrocarbon radical and in which, inthe preferred form, X is OCH3. The preparation of this reagent isdescribed in my copending U. S. applications Serial No. 633,873, filedDecember 8, 1945, now U. S. Patent No. 2,541,091, and

Serial No. 633,874, filed December 8, 1945, now

mide, cuprous chloride, cuprous iodide, cuprous cyanide, cupricchloride, cobalt chloride, ferric chloride, and cupric bromide aresatisfactory catalysts, but anhydrous cupric chloride is preerred. Theproduct of this reaction, before hydrolysis, is present in solution andcorresponds to the formula in which M, Y, R, and X have the same meaningas above and in which in the preferred form MY is MgBr, R isnonexistent, and X is OCI-I3.

Hydrolysis of the reaction mixture containing Compound III in solutionmay be accomplished by any of the usual methods used for the hydrolysisof a Grignard reaction mixture, such as treating with dilute acids,Water, or preferably with a solution of a Water soluble ammonium saltwhich has been made slightly alkaline, pH 7.5-9.0, by the addition ofaqueous ammonium hydroxide. Upon hydrolysis of Compound III, Compound Iis produced.

After the hydrolysis is complete, it is necessary to remove unreactedreagent from the reaction mixture, and for this purpose, a base isemployed. Inorganic bases such as alcoholic sodium hydroxide andpotassium hydroxide or organic bases such as diethyl amine may be used.

The following equations illustrate the preferred process for thepreparation of Compound 1:

CH: CH:

H2 "CH3 Compound 11 CH: Compound II ZCHz( I=CHCHzX CH3 CH3 CH3 CH3Compound III hydrolysis Compound III CH3 CH3 CH: CH:

H2 CH:

Compound I An alternate procedure for preparing Compound I is to reactthe beforementioned reagent i z-omc=onomx with sodium, potassium,lithium, or calcium and then to react this with RMgZ, where Z is ahalogen and R" is a hydrocarbon radical, to form an intermediarycompound:

The acetylenic bond of Compound I may be reduced to a double bond; theresulting substance has the following structure:

Compound IV where X has the same significance as before.

In the conversion of Compound I to Compound IV, catalytic hydrogenationmay be used, and in this case it has been found that poisoned palladiumsupported on calcium carbonate, Raney nickel, or poisoned Raney nickelare satisfactory. Raney nickel may be satisfactorily poisoned by acadmium salt, a zinc salt which forms a soluble complex in methylalcohol with an amine, piperidine, pyridine, thiourea, aminothiazoles,or a combination of zinc acetate and piperidine; however, Raney nickelpoisoned by a combination of zinc acetate and piperidine is thepreferred catalyst. It is also possible to reduce by chemical reagents,but catalytic hydrogenation is preferred.

In the following specific examples for carrying out the reactionsoutlined above, the preparation of Compound I by the preferred routewill be used as illustrative, and the compounds will be referred to bynumbers used in the above description.

The folowing examples are given merely to illustrate specific ways inwhich the invention may be practiced, and it is to be understood thatthe invention is not to be restricted or limited thereby.

6 EXAMPLE I Conversion of a-ethynyZ-s-ionol into its Grignard derivativeOne mole proportion (218 grams) of a-ethynylc-ionol was placed in aglass flask. Then there were added thereto about 600 grams of anhydrousethyl ether which dissolved said u-ethynylc-ionol. This solution wascontinuously agitated or stirred while there were gradually addedthereto two mole proportions of a Grignard reagent and in thisillustration 267 grams of CzHsMgBr dissolved in 700 cc. of anhydrousethyl ether. After completion of this addition, the mixture was heatedto boiling while continuously stirred and in a constant state ofagitation and was maintained in this state of boiling under a refluxcondenser for a period of approximately thirty minutes, whereby a novelreaction product which was dissolved in said ethyl ether was produced.It may be isolated therefrom in any convenient manner and has thefollowing formula:

I OMgBr Hg CH3 EXAMPLE II Conversion of e-ethynyl-p-ionol into itslithium derivative The same procedure as that set forth in Example I wasfollowed except that two moles (44 grams) of methyl lithium weresubstituted for the ethyl magnesium bromide of Example I. The resultantreaction product had a low solubility factor in ethyl ether andseparated out as a crystalline solid and has the following formula:

EXAIMPLE III Conversion of a-eth11nyl-/3-ionol into its Grignardderivative The same procedure as that set forth in Example I wasfollowed except that two moles (7.50 grams) of methyl magnesium chloridewere substituted for the ethyl magnesium bromide of Example I. Theresultant reaction product had a low solubility factor in ethyl etherand sep arated out as a crystalline solid and has the following formula:

CH3 CH3 J- CH=CH'-( 3CEC-Mg c1 EXAMPLE IV Conversion ofa-ethynyl-c-ionol to its zinc iodide derivative The same procedure asthat set forth in Erample I was followed except that two moles (415grams) of methyl zinc iodide were substituted for the ethyl magnesiumbromide of Example I.

This novel reaction product was partially soluble in ethyl ether andmaybe isolated therefrom in any convenient manner and has the followingformula:

OH: CH:

(1 H; H. GH=CHCCEC-Znl 02:11 H: CH:

EXANIPLE V Condensation of a-ethynyZ-p-ionol double Grinnard with1-chloro-2-methyl-4-methoxybutene-Z to form (Compound IIImethoa:y)

To the reaction mixture from Example I containing Compound II in thepreferred form and which had been allowed to cool to room temperaturewas added one mole proportion of the methyl ether of the 1,4chlorohydrin of isoprene, followed by the addition of approximately 5grams of anhydrous cupric chloride as a catalyst. The mixture wasstirred under a reflux condenser and heated to boiling and kept at aboiling temperature under reflux four to eight hours, and then allowedto cool to room temperature and stirred for fifteen hours. At this pointtwo layers were formed.

Cuprous bromide may be used to catalyze this condensation. When cupricchloride was used, a series of color changes from dark red to yellowoccurred within the first few minutes, but when cuprous bromide wasused, there were no color changes, but a gradual solution of the solidoccurred. After approximately three-fourths of an hour, a heavy lowerliquid layer was formed. Refiuxing with stirring was continued at roomtemperature for fifteen hours in either case. .By this time the lowerliquid layer had changed to a tacky reddish mass.

EXAMPLE VI Hydrolysis of Compound III (methoxy) to obtain Compound I'(methoxy) The reaction product from Example V was hydrolyzed by firstchilling the stirred fiask contents to 40 C. and adding slowly andcautiously 150 cc. of 30% aqueous ammonium chloride. The reactionmixture was allowed to come up slowly to room temperature with stirringand was then stirred until all solid matter had dissolved.

The hydrolysis may be made with aqueous acetic acid, and in this case,the reaction prodnot from Example V was cooled to C., and

CJI

acid was completed. In either case the mass was allowed to come to roomtemperature and was filtered. The filtrate separated into two layers, anaqueous layer and an ether layer. The ether layer was separated from theaqueous layer and washed with water and then with sodium bicarbonatesolution to neutralize any residual acetic acid.

A 5% aqueous solution of ammonium acetate may also be used to hydrolyzethe reaction product from Example V by following the same conditions aswhen aqueous acetic acid is used.

The neutral reaction product obtained by the hydrolysis was treated toremove therefrom any unreacted methyl ether of the 1,4 chlorohydrin ofisoprene. This was done by adding an organic base and in this example byadding diethyl amine, 73 grams (1 mole), to the wet etheral solution ofthe crude condensation product as directly obtained from the hydrolysis.The amine being higher boiling than ether, the ether was removed bydistillation at atmospheric pressure. This solution was allowed to standat room temperature for eight to twenty-four hours and was then pouredinto a large volume of water, whereupon liquid oily particles separatedout and were extracted with ethyl ether which dissolved the same. Thisether solution was separated and removed from the aqueous portion of themix and was then washed with water several times, and finally with anaqueous solution of sodium carbonate. The solution was dried withanhydrous potassium carbonate or other suitable drying agent andfiltered; the filtrate was recovered and concentrated under vacuum atroom temperature. The concentrate consisted essentially of Compound Iand was distilled under high vacuum at C. to C. and 0.001 mm. of mercurypressure. This material had a refractive index at 20 C. of 1.5116 andshowed absorption in the ultra violet with a maximum at 2370 A and amolecular coefficient of extinction at this wave length of 6,026. Aformula such as that of Compound I has a theoretical value for carbon of79.69% and of 10.19% for hydrogen; 79.63% carbon and 10.22% hydrogenwere found on analysis.

It has been found that if the wet ether solution is concentrated withoutfirst adding a base, the moisture present eventually hydrolyzes someunreacted methyl ether of the 1,4 chlorohydrin of isoprene which ispresent in excess, and the free hydrogen chloride thus formed, even intraces, causes partial dehydration of the condensation product. Byconcentrating in the presence of an amine such hydrolysis may beprevented since any free hydrogen chloride formed is immediatelyneutralized by the amine present and thus prevents dehydration. ,Onsmall experiments where the time required to remove the ether isrelatively short, the presence of the amine is not necessary since theether is fully removed before any of the chlorohydrin has a chance tohydrolyze and the product is treated at that point to remove theunreacted chlorohydrin as indicated below. However, on largerexperiments, the time required to remove the ether is naturally muchlonger, and the chlorohydrin has a chance to hydrolyze. Under suchconditions there must always be amine present or some other base toneutralize any hydrogen chloride that may be formed.

EXAMPLEVII Hydrogenation of Compound I (methoxy) by the use of poisonedpalladium as a catalyst to produce Compound IV (methoxy) Compound I(methoxy) obtained by proceeding as in Example VI was dissolved in fiveto ten times its volume of anhydrous methanol containing .07 gram ofzinc acetate and 10 cc. of diethyl amine per cc. of the said solution ofCompound I in methanol. To this solution was then added 10 grams ofpowdered activated charcoal Norite" containing one gram of palladiummetal uniformly distributed on its surface. This mixture was shaken tothoroughly distribute the components with respect to each other;' Theentire mixture was then shaken under an atmosphere of hydrogen gas atatmospheric pressure. A small amount of hydrogen was absorbed in thisstep. To this mixture were added 30 grams of calcium carbonate powdercontaining 0.36 gram of palladium hydroxide uniformly distributed on itssurface, and this mixture was again subjected to shaking in anatmosphere of hydrogen at atmospheric pressure. Absorption of hydrogenwas measured continuously as it was being added. When one mole ofhydrogen had been absorbed, this operation was stopped and the mass wasfiltered; the filtrate was recovered and consisted essentially of anovel compound dissolved in methanol and having the following generalformula:

This methanol solution was poured into a large volume of water whichdissolved the methanol and separated the oil therefrom. To this massthere was added ethyl ether which dissolved the oil. This mass separatedinto two layers, an ether layer and an aqueous layer. The ether layerwas separated from the aqueous layer and washed several times withwater; it was then dried with potassium carbonate or any other suitabledrying agent, filtered, and the filtrate was recovered and concentratedunder vacuum at room temperature. The concentrate was then subjected tohigh vacuum distillation. The product distilled at 105 C. to 115 C. at0.001 of mercury pressure. The fraction distilling at the abovetemperature range weighed 260 grams. This fraction has carbon andhydrogen values corresponding to the calculated values of a compoundhaving the formula of Compound IV (methoxy). Calculated carbon=79.19%,found: 79.36%; calculated hydrogen=10.76%, found: 10.73%. This fractionis a golden yellow viscous liquid whose ultra-violet spectrum shows anabsorption band with a maximum at 2360 A and a molecular coeficient ofextinction at this wave length of 6,500; it has an index of refractionat 20 C. of 1.5087. It shows the same growthpromoting properties invitamin A deficient animals as does natural vitamin A.

EXAMPLE VIII Hydrogenation of Compound I (memory) by the,

use of poisoned Raney nickel as a cataZg st'to produce Compound IV(methory) The crude condensation product from Example VI was dissolvedin five to ten times its volume of methanol and 2 cc. of pyridine and 6grams of wet Raney nickel paste (Gilman Paint and Varnish Company) wasthen added. This mixture was shaken under hydrogen until the theoreticalamount had been absorbed. After removal of the catalyst by filtration,the orange lected and this was Compound IV (methoxy), a pale yellow,mobile liquid having a refractive index at 25 C. of 1.5070.

Another reduction of the crude condensation product of Compound I toCompound IV was made in the same way as above using 150 cc. of

.methyl alcohol as the solvent, 5 grams of Raney nickel as the catalystand a combination of 5 cc. piperidine and 300 mg. of zinc acetate as thepoison for the catalyst. This resulted in a product having the samephysical properties as shown above; the yield was also approximately thesame.

EXAMPLE IX periodof onehour, were added two grams of cuprous bromide.The black color of the solution disappeared immediately, and the colorwas then light yellow. Eighteen grams of the acetoxy compound, in 20 cc.of ether, were added to the Grignard over a period of about ten minutes,and a second heavy layer appeared within a very short time after theaddition was complete. The

solution was stirred under nitrogen for eighteen hours and then cooledto -20 C. A saturated solution of ammonium chloride was carefully added,and the solution was then allowed to come up to room temperature. Thesolution was filtered, washed with water, then with ether and ammoniumchloride aqueous solution alternately several times. The solution wasagain filtered, and the ether layer concentrated under vacuum. Theresidual oil was dissolved in 50 cc. of ethyl alcohol and 50 cc. ofdiethyl ethanol amine. This solution was allowed to stand at roomtemperature for a period of two days under nitrogen and in the dark. Thedark opaque reaction mixture was poured into several times its volume ofbrine solution and extracted with petroleum ether. The petroleum etherlayer was washed with dilute acetic acid and then with water and finallywith sodium bicarbonate solution. The solution was dried over potassiumcarbonate and concentrated under vacuum. The product of this reactionhas the following formula:

EXAMPLE X Reduction of Compound I (acetory) The concentrate obtainedfrom Example X was dissolved in cc. of t-butyl alcoholl One gram ofcatalytic material consisting of palladium on charcoal wherein 10% ofthe composition palladium, 2 cc. of water, and 10 cc of diethyl aminewas added to the concentrate as a catalyst. The concentrate plus thecatalyst mixture was shaken in the presence of hydrogen until an amountof hydrogen slightly in excess of the theoretical amount required toreduce an acetylenic bond to an ethylenic bond had been absorbed. Thecatalyst was then filtered off, and the resulting filtrate was pouredinto brine. This mixture was extracted several times with ether, washedwell with water, and the ether solution was dried over potassiumcarbonate. The ether solution was filtered and concentrated under vacuumand finally distilled at 10- mm. Three fractions were taken.

The first fraction came over at 60 C. to 105 C. and had a refractiveindex at 27.7 C. of 1.5128. The second fraction came over at 105 C. to110 C. and had a refractive index at 27.7 C. of 1.5278. The thirdfraction came over at 110 C. to 150 C. and had a refractive index at27.7 C. of 1.5390. The third fraction represents the reduced product andis represented by the following formula:

CH3 CH3 Compound IV (acctoxy) H2 in which X is selected from the groupconsisting of OR and and R is a lower alkyl radical, to produce acompound of the formula CH3 CH2 wherein X has the same significance asabove.

2. The method comprising hydrogenating a compound of the formula CH3 CH3in which R is a lower alkyl radical, to produce a compound of theformula CH: CH;

in which R is a lower alkyl radical.

12 3. The method comprising hydrogenating a compound of the formula CH:CH;

(311a (IE3 IE1 CH=CH(]1CEC-CH:C=CHOHz-O-CH;

OH H CH| Hz to produce a compound of the formula:

CH3 CH3 a (311: 112 CH=CHC-CH=CH-OHa-C=CHCHz-O-CH:

1 OH H: CH:

4. The method comprising reacting a-ethynylfl-ionol with ametallo-organic compound of the class consisting of lithium, magnesium,and zinc alkyls and magnesium and zinc alkyl halides, in which eachalkyl is of low molecular weight, to produce a compound in which thehydrogen of the hydroxyl group and the hydrogen of the acetylenic groupare removed and the oxygen of the hydr xyl group and the terminal carbonof the acetylenic group are each bound to a metal.

5. A method according to claim 4 in which the metallo-organic compoundis a magnesium alkyl halide.

6. A method according to claim 4 in which the metallo-organic compoundis methyl lithium.

7. A method according to claim 4 in which the metallo-organic compoundis ethyl magnesium bromide.

8. The method comprising reacting a-ethynylfi-ionol with ametallo-organic compound of the class consisting of lithium, magnesium,and zinc alkyls and magnesium and zinc alkyl halides, in which eachalkyl is of low molecular weigh to produce a compound in which thehydrogen of the hydroxyl group and the hydrogen of the acetylenic groupare removed and the oxygen of the hydroxyl group and terminal carbon ofthe acetylenic group are each bound to a metal; and reacting thereaction product with a compound of the formula CH: Z-CHz( 3=CHCHzXwherein Z is halogen, X is selected from the group consisting of-OR. and

and 'R is a lower alkyl radical, to produce a compound of the formula inwhich X has the same significance as above.

9. A method according to claim 8 in which Z is chlorine.

10. A method according to claim 8 in which X is -OR and R is a methylradical.

11. The method comprising reacting a-ethynylp-ionol with ametallc-organic compound of the class consisting of lithium, magnesium,and zinc alkyls and magnesium and zinc alkyl halides, in which eachalkyl is of low molecular weight, to produce a compound in which thehydrogen of the hydroxyl group and the hydrogen of the acetylenic groupare removed and the oxygen of the hydroxyl group and the terminal carbonof the acetylenic group are each bound to a metal; reacting the reactionproduct with a compound of the formula and R is a lower alkyl radical,to produce a compound of the formula in which X has the samesignificance as above; and hydrogenating the acetylenic loond to producea compound of the formula in which X has the same significance as above.

12. A method according to claim 11 in which the metallo-organic compondis a magnesium alkyl halide.

13. The method comprising reacting a-ethynylfi-ionol with ametallo-organic compound of the class consisting of lithium, magnesium,and zinc alkyls and magnesium and zinc alkyl halides, in which eachalkyl is of low molecular weight to produce a compound in which thehydrogen of the acetylem'c group are removed and the oxygen of thehydroxyl group and the terminal carbon of the acetylenic group are eachbound to a metal; reacting the reaction product with a compound of theformula 14 wherein Z is halogen, X is selected from the group consistingof -OR and n 5 O C R and R is a lower alkyl radical, to produce acompound of the formula CH: OH:

in which X has the same significance as above; hydrogenating theacetylenic bond to produce a compound of the formula in which X has thesame significance as above; and dehydrating to produce a conjugatedpentaene having vitamin A activity.

14. A method according to claim 13 in which the metallo-organic compoundis a magnesium alkyl halide.

15. A method according to claim 13 in which Z is chlorine.

Kipping et al.: Chemistry and Industry," August 26, 1939. Vol. 58, page802.

Oroshink: Jour. Am. Chem. 800., vol. 67 (1945), pages 1627, 1628.

Heilbron: "Jour. Chem. Soc. (London), 1948, page 387.

1. THE METHOD COMPRISING HYDROGENATING A COMPOUND OF THE FORMULA